This proposal is designed to investigate the CD8+T lymphocyte response to type A Influenza virus and the factors which regulate the activation and differentiation CD8+T cells into activated cytolytic T lymphocyte (CTL) effectors. The experimental approach is based on our recent observation that the weak (subdominant) response to the type A influenza hemagglutinin in the mouse is due to the inability of immune CTL precursors to fully differentiate into activated CTL effectors in response to virus infection. Specific Aim 1 examines the proliferative potential of CD8+ T cells responding to this subdominant influenza hemagglutinin epitope, the kinetics of expression of selected cell surface markers associated with the activation, differentiation and memory phenotype development by these virus specific CD8+ T cells as well as the expression of CTL effector activity i.e. cytolytic machinery and cytokine gene expression. Related studies will elucidate the mechanism underlying the inability of these subdominant CD8+T cells to bind epitope specific MHC Class I tetramers and the role of TCR arrangement on the surface of these activated CD8+T cells in regulating T cell activation and tetramer binding. Specific Aim 2 focuses on the role of self peptides in controlling the activation state and responsiveness of these CD8+T cells to antigen and analyses the impact of repeat exposure to the Influenza hemagglutinin epitope on the state of differentiation and the expression of effector activity by these subdominant CD8+T cells. The proposed studies should provide new information on this novel mechanism of control of the CD8+T cell response to Influenza Virus infection. The proposed studies should also help elucidate the effect of vaccination on the generation of an effective CD8+T cell memory response to this important human pathogen. In addition these experiments may provide insight into the process of CD8+T cell activationJdifferentiatjon into CTL effector cells.